Prenatal Progestin Exposure-Mediated Oxytocin Suppression Contributes to Social Deficits in Mouse Offspring

Area of Science:

• Neuroscience
• Endocrinology
• Developmental Biology

Background:

• Maternal hormone exposure is linked to autism spectrum disorders (ASD).
• Oxytocin (OXT) is a neuropeptide crucial for social behavior, implicated in ASD etiology.
• The precise mechanisms linking prenatal hormone exposure to ASD-related neurodevelopmental changes are not fully understood.

Purpose of the Study:

• To investigate the role of oxytocin (OXT) in social deficits observed in offspring following prenatal progestin exposure.
• To explore the epigenetic mechanisms underlying OXT suppression by progestins.
• To assess potential therapeutic interventions for progestin-induced social deficits.

Main Methods:

• In vitro studies using hypothalamic neurons to examine epigenetic changes on the OXT promoter after progestin exposure.
• In vivo studies using mouse models exposed prenatally to medroxyprogesterone acetate (MPA).
• Assessment of social behaviors, OXT levels, estrogen receptor beta (ERβ) expression, and effects of OXT peptide injection.

Main Results:

• Transient progestin exposure induced persistent epigenetic changes on the OXT promoter, leading to sustained OXT suppression.
• Prenatal MPA exposure caused social deficits in mouse offspring, including impaired social interaction and abilities.
• OXT deficiency partly mimicked these deficits, while postnatal ERβ expression or OXT injection partially ameliorated them.
• OXT did not affect anxiety-like behaviors induced by prenatal MPA exposure.

Conclusions:

• Prenatal progestin exposure, specifically MPA, contributes to social deficits in offspring through the suppression of oxytocin (OXT).
• Epigenetic modifications at the OXT promoter are a key mechanism mediating this effect.
• Targeting the OXT pathway, potentially via ERβ, offers a therapeutic strategy for social deficits associated with prenatal hormone exposure.